title: Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice.
abstract: BACKGROUND
  CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model.
  
  
  METHODS
  Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney.
  
  
  RESULTS
  Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment.
  
  
  CONCLUSIONS
  Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Seok
authors.forename: Eun Soo
authors.initials: ES
authors.lastname: Lee
authors.forename: Geun Tae
authors.initials: GT
authors.lastname: Kim
authors.forename: Miri
authors.initials: M
authors.lastname: Hyun
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Lee
authors.forename: Sheldon
authors.initials: S
authors.lastname: Chen
authors.forename: Ran
authors.initials: R
authors.lastname: Choi
authors.forename: Hong Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.forename: Choon Hee
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000419:Albuminuria / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005434:Flow Cytometry; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2
keywords: CCL2; CCR2; albuminuria; diabetic nephropathy